Graduate Thesis Or Dissertation
 

Approaches to the synthesis of methymycin

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  • Several approaches to the synthesis of methymycin were investigated. Segment A (39), containing functionality corresponding to C-9, 10, and 11 of methynolide was made in six steps from propionaldehyde in an overall yield of 37%. Oxidation of 34 with silver nitrate gave 35 which, upon hydroxylation with hydrogen peroxide, gave the erythro isomer of dihydroxy acid 36. This acid was resolved with brucine and its absolute configuration determined by Horeau's method. The (+) acid was found to have R,R configuration. This substance was converted to its acetonide (+)-37, which was reduced with lithium aluminium hydride to give (+)-38. Oxidation of (+)-38 with Collins' reagent gave (+)-39. An approach to the B segment (31), corresponding to C₁₋C₈ of methymycin, from dicyclopentadiene was investigated. Dicyclopentadiene, on reaction with selenium dioxide followed by oxidation by Jones' reagent, gave 53. Treatment of 53 with methyl magnesium iodide in the presence of cuprous chloride gave 54. The latter was converted to ketal 55, which was subjected to Lemieux-von Rudloff oxidation to give diacid 56. This diacid was converted to its diester 57 which, on reduction with lithium aluminium hydride, gave diol 58. Efforts to reduce the two primary alcohol functions to methyl groups were unsuccessful. The ketal 55 was converted to the dialdehyde 63 with sodium metaperiodate and osmium tetroxide. However, attempted tosylhydrazone formation led to complex mixtures. An alternative approach via cycloaddition of 2,4-dibromo- 3-pentanone (64) to furan, using zinc-copper couple, gave a mixture of adducts 65, 66 and 67 in a 8:1:1 ratio. Efforts at reducing the ketone in these cycloadducts to a methylene group led to recovery of starting material. The mixture of cycloadducts was reduced with sodium borohydride to yield alcohols 76 and 77 in a 2:1 ratio. On treatment of this mixture with methanesulfonyl chloride only the exo mesylate 78 was formed. Attempts to displace this mesylate with various reducing agents were unsuccessful. Hydroboration of 65, followed by oxidation, led to diketone 82. However efforts directed towards a Baeyer-Villiger oxidation of this substance led to decomposition. A cycloaddition approach to methynolide, using 2-furfuryl benzyl ether (84), was also investigated. The reaction of 64 with 84 in the presence of zinc-copper couple gave 85, reduction of which with sodium borohydride led to alcohol 86. Epoxidation of 86 with m-chloroperbenzoic acid gave alcohols 87 and 88 in a 85:15 ratio. The major isomer was converted to its mesylate 89, but attempts to displace the mesylate reductively were unsuccessful. Alcohol 86 was converted to its mesylate 97 which, on reaction with m-chloroperbenzoic acid, gave epoxide 98. Reduction of 98 with lithium aluminium hydride afforded a mixture of olefinic alcohols assigned as 99 which, upon hydroboration, gave 100. Attempts at oxidizing alcohols 99 and 100 were unsuccessful. Also, an attempt to transform the alcohol 86 to bromohydrin 106 led instead to the bridged bromoethers 109 and 110 in a 1:1 ratio. Treatment of the mixture of 109 and 110 with lithium dimethylcuprate regenerated 86. Cycloaddition of 64 with 3-methylfuran was briefly investigated and was found to yield 112. Hydroboration of 112, followed by oxidation with sodium dichromate, gave diketone 116 which, on treatment with sodium methoxide, gave the epimeric diketone 117. An attempted Baeyer-Villiger oxidation of 117 with trifluoroperacetic acid was unsuccessful
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